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NM_003977.4(AIP):c.896C>T (p.Ala299Val)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely benign(3);Uncertain significance(2)

Review status:
criteria provided, conflicting interpretations
Submissions:
7 (Most recent: Nov 4, 2021)
Last evaluated:
Nov 3, 2021
Accession:
VCV000041214.9
Variation ID:
41214
Description:
single nucleotide variant
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NM_003977.4(AIP):c.896C>T (p.Ala299Val)

Allele ID
49636
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
11q13.2
Genomic location
11: 67490896 (GRCh38) GRCh38 UCSC
11: 67258367 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000011.9:g.67258367C>T
NC_000011.10:g.67490896C>T
NG_008969.1:g.12863C>T
... more HGVS
Protein change
A299V, A240V
Other names
-
Canonical SPDI
NC_000011.10:67490895:C:T
Functional consequence
-
Global minor allele frequency (GMAF)
0.00060 (T)

Allele frequency
The Genome Aggregation Database (gnomAD) 0.00065
Trans-Omics for Precision Medicine (TOPMed) 0.00084
The Genome Aggregation Database (gnomAD), exomes 0.00056
The Genome Aggregation Database (gnomAD) 0.00041
1000 Genomes Project 0.00060
Exome Aggregation Consortium (ExAC) 0.00043
Trans-Omics for Precision Medicine (TOPMed) 0.00071
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00100
Links
ClinGen: CA344210
dbSNP: rs148986773
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Likely benign 3 criteria provided, multiple submitters, no conflicts May 28, 2021 RCV001357152.3
Uncertain significance 1 criteria provided, single submitter Feb 5, 2020 RCV000571818.3
Conflicting interpretations of pathogenicity 3 criteria provided, conflicting interpretations Nov 3, 2021 RCV000034113.5
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
AIP - - GRCh38
GRCh37
378 395

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Likely benign
(Apr 27, 2017)
criteria provided, single submitter
Method: clinical testing
Somatotroph adenoma
Allele origin: germline
Illumina Clinical Services Laboratory,Illumina
Accession: SCV000373585.3
Submitted: (Feb 20, 2020)
Evidence details
Publications
PubMed (4)
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
Likely benign
(May 28, 2021)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000521287.5
Submitted: (Jun 28, 2021)
Evidence details
Comment:
This variant is associated with the following publications: (PMID: 27267386, 28220018, 29074612, 22720333, 27253664, 27535533, 27153395, 20506337, 24423289, 17360484)
Uncertain significance
(Nov 03, 2021)
criteria provided, single submitter
Method: clinical testing
Somatotroph adenoma
Allele origin: germline
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002009986.1
Submitted: (Nov 04, 2021)
Evidence details
Uncertain significance
(Feb 05, 2020)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Ambry Genetics
Accession: SCV000664959.3
Submitted: (Nov 30, 2020)
Evidence details
Publications
PubMed (11)
Comment:
The p.A299V variant (also known as c.896C>T), located in coding exon 6 of the AIP gene, results from a C to T substitution at nucleotide … (more)
Likely benign
(Dec 08, 2020)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
Invitae
Accession: SCV001605607.1
Submitted: (Jan 07, 2021)
Evidence details
unknown
(Jun 21, 2012)
no assertion criteria provided
Method: curation
AIP-Related Familial Isolated Pituitary Adenomas
Allele origin: not provided
GeneReviews
Accession: SCV000058043.2
Submitted: (Mar 26, 2013)
Evidence details
Comment:
Converted during submission to Uncertain significance.
Likely benign
(-)
no assertion criteria provided
Method: clinical testing
not provided
Allele origin: unknown
Department of Pathology and Laboratory Medicine,Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001552523.1
Submitted: (Mar 31, 2021)
Evidence details
Comment:
The AIP p.A299V variant was identified in 1 of 72 proband chromosomes (frequency: 0.0139) from endocrine neoplasia-predisposition patients from the Netherlands who were negative for … (more)

Functional evidence

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There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Citations for this variant

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Title Author Journal Year Link
<i>AIP</i> Familial Isolated Pituitary Adenomas Korbonits M - 2020 PMID: 22720333
Utility of Population-Level DNA Sequence Data in the Diagnosis of Hereditary Endocrine Disease. Newey PJ Journal of the Endocrine Society 2017 PMID: 29308445
<i>AIP</i> mutations in Brazilian patients with sporadic pituitary adenomas: a single-center evaluation. Araujo PB Endocrine connections 2017 PMID: 29074612
Role of Phosphodiesterases on the Function of Aryl Hydrocarbon Receptor-Interacting Protein (AIP) in the Pituitary Gland and on the Evaluation of AIP Gene Variants. Hernández-Ramírez LC Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 2017 PMID: 28427099
Germline variants in familial pituitary tumour syndrome genes are common in young patients and families with additional endocrine tumours. De Sousa SMC European journal of endocrinology 2017 PMID: 28220018
cAMP-specific PDE4 phosphodiesterases and AIP in the pathogenesis of pituitary tumors. Bolger GB Endocrine-related cancer 2016 PMID: 27267386
Rapid Proteasomal Degradation of Mutant Proteins Is the Primary Mechanism Leading to Tumorigenesis in Patients With Missense AIP Mutations. Hernández-Ramírez LC The Journal of clinical endocrinology and metabolism 2016 PMID: 27253664
Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer. Maxwell KN American journal of human genetics 2016 PMID: 27153395
Genetic mutations in sporadic pituitary adenomas--what to screen for? Lecoq AL Nature reviews. Endocrinology 2015 PMID: 25350067
Clinical experience in the screening and management of a large kindred with familial isolated pituitary adenoma due to an aryl hydrocarbon receptor interacting protein (AIP) mutation. Williams F The Journal of clinical endocrinology and metabolism 2014 PMID: 24423289
Characterization of aryl hydrocarbon receptor interacting protein (AIP) mutations in familial isolated pituitary adenoma families. Igreja S Human mutation 2010 PMID: 20506337
Germline inactivating mutations of the aryl hydrocarbon receptor-interacting protein gene in a large cohort of sporadic acromegaly: mutations are found in a subset of young patients with macroadenomas. Cazabat L European journal of endocrinology 2007 PMID: 17609395
Molecular diagnosis of pituitary adenoma predisposition caused by aryl hydrocarbon receptor-interacting protein gene mutations. Georgitsi M Proceedings of the National Academy of Sciences of the United States of America 2007 PMID: 17360484

Text-mined citations for rs148986773...

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These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 27, 2021